The differential vulnerability of dopaminergic neurons of the substantia nigra pars compacta (SNc) is a critical and unresolved question in Parkinson´s disease. Studies in mice show diverse susceptibility of subpopulations of nigral dopaminergic neurons to various toxic agents. In the primate midbrain, the molecular phenotypes of dopaminergic neurons and their differential vulnerability are poorly characterized. We performed a detailed histological study to determine the anatomical distribution of different molecular phenotypes within identified midbrain neurons and their selective vulnerability in control and MPTP-treated monkeys. In the ventral tier of the SNc (nigrosome), neurons rich in Aldh1a1 and Girk2 are intermingled, whereas calbindin is the marker that best identifies the most resilient neurons located in the dorsal tier and ventral tegmental area, recapitulating the well-defined dorsoventral axis of susceptibility to degeneration of dopaminergic neurons. In particular, a loss of Aldh1a1+ neurons in the ventral SNc was observed in parallel to the progressive development of parkinsonism. Aldh1a1+ neurons were the main population of vulnerable dopaminergic nigrostriatal-projecting neurons, while Aldh1a1- neurons giving rise to nigropallidal projections remained relatively preserved. Moreover, bundles of entwined Aldh1a1+ dendrites with long trajectories extending towards the substantia nigra pars reticulata emerged from clusters of Aldh1a1+ neurons and colocalized with dense cannabinoid receptor 1 afferent fibers likely representing part of the striatonigral projection that is affected in human disorders, including Parkinson´s disease. In conclusion, vulnerable nigrostriatal-projecting neurons can be identified by using Aldh1a1 and Girk2. Further studies are needed to define the afferent/efferent projection patterns of these most vulnerable neurons.

黑质致密部(SNc) 多巴胺能神经元的不同脆弱性是帕金森病的一个关键且尚未解决的问题。对小鼠的研究表明，黑质多巴胺能神经元亚群对各种有毒物质具有不同的敏感性。在灵长类中脑中，多巴胺能神经元的分子表型及其不同的脆弱性尚不清楚。我们进行了详细的组织学研究，以确定已识别的中脑神经元内不同分子表型的解剖分布及其在对照猴和 MPTP 治疗猴中的选择性脆弱性。在 SNc（黑质体）的腹侧层，富含 Aldh1a1 和 Girk2 的神经元混合在一起，而 calbindin 是最好地识别位于背侧层和腹侧被盖区的最具弹性神经元的标记物，概括了明确的背腹轴多巴胺能神经元变性的易感性。特别是，在帕金森病的进展过程中，观察到腹侧 SNc 中 Aldh1a1+ 神经元的丢失。 Aldh1a1+ 神经元是脆弱的多巴胺能黑质纹状体投射神经元的主要群体，而产生黑质苍白球投射的 Aldh1a1- 神经元仍然相对保留。此外，一束缠绕的Aldh1a1+树突束，其长轨迹延伸至黑质网状部，从Aldh1a1+神经元簇中出现，并与密集的大麻素受体1传入纤维共定位，可能代表了受人类疾病（包括帕金森病）影响的纹状体黑质投射的一部分疾病。 总之，可以使用 Aldh1a1 和 Girk2 来识别脆弱的黑质纹状体投射神经元。需要进一步的研究来定义这些最脆弱神经元的传入/传出投射模式。